Increasing tumoral 5-fluorouracil concentrations during a 5-day continuous infusion: a microdialysis study

Purpose: Response to anticancer therapy is believed to be directly related to the concentration of the anticancer drug in the tumor itself. Assessment of intra-tumor drug pharmacokinetics can be helpful to gain more insight into mechanisms involved in the (in)sensitivity of tumors to anticancer therapy. We explored the pharmacokinetics of 5-fluorouracil in both plasma and tumor tissue during a 5-day continuous infusion of 5-fluorouracil in patients with cancer. Sampling for measurement of 5-fluorouracil in tumor tissue was performed using microdialysis. Experimental design: In seven patients with an accessible (sub)cutaneous tumor treated with a continuous 5-fluorouracil infusion, plasma and microdialysate samples from tumor and normal adipose tissue were collected over a period of 5 days. Results: For six patients, drug concentrations in both tumor tissue and plasma were available. Concentration-time curves of unbound 5-fluorouracil were lower in tumor tissue compared to the curves in plasma, but exposure ratios of tumor tissue versus plasma increased during the 5-day infusion period. The presence of circadian rhythmicity of 5-fluorouracil pharmacokinetics in the tumor itself was demonstrated as 5-fluorouracil concentrations in tumor extracellular fluid were higher during the night than during daytime. Conclusion: Microdialysis was successfully employed in patients with cancer during a continuous 5-day 5-fluorouracil infusion. Plasma and tumor pharmacokinetics of 5-fluorouracil differed substantially with increasing 5-fluorouracil concentrations in tumor over time, possibly resulting from a lowered interstitial fluid pressure by 5-fluorouracil itself. This microdialysis 5-fluorouracil model might be useful to monitor the effect of drug delivery modulating strategies in future studies

Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling

Mutations in the estrogen receptor gene ( ESR1), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing data from the same samples of 101 ER-positive/HER2-negative MBC patients who underwent a tumor biopsy prior to the start of a new line of treatment for MBC (CPCT-02 study, NCT01855477) to analyze the downstream effects of DNA alterations previously linked to endocrine resistance, thereby gaining a better understanding of the associated mechanisms. Hierarchical clustering was performed using expression of ESR1 target genes. Genomic alterations at the DNA level, gene expression levels, and last administered therapy were compared between the identified clusters. Hierarchical clustering revealed two distinct clusters, one of which was characterized by increased expression of ESR1 and its target genes. Samples in this cluster were significantly enriched for mutations in ESR1 and amplifications in FGFR1 and TSPYL. Patients in the other cluster showed relatively lower expression levels of ESR1 and its target genes, comparable to ER-negative samples, and more often received endocrine therapy as their last treatment before biopsy. Genes in the MAPK-pathway, including NF1, and ESR1 transcriptional regulators were evenly distributed. In conclusion, RNA sequencing identified a subgroup of patients with clear expression of ESR1 and its downstream targets, probably still benefiting from ER-targeting agents. The lower ER expression in the other subgroup might be partially explained by ER activity still being blocked by recently administered endocrine treatment, indicating that biopsy timing relative to endocrine treatment needs to be considered when interpreting transcriptomic data

Application of prolonged microdialysis sampling in carboplatin-treated cancer patients

Purpose: To better understand the mechanisms underlying (in)sensitivity of tumors to anticancer drugs, assessing intra-tumor drug pharmacokinetics (PKs) could be important. We explored the feasibility of microdialysis in tumor tissue for multiple days in a clinical setting, using carboplatin as model drug. Methods: Plasma and microdialysate samples from tumor and adipose normal tissues were collected up to 47 h after dosing in eight carboplatin-treated patients with an accessible (sub)cutaneous tumor. Results: Pharmacokinetics were evaluable in tumor tissue in 6/8 patients and in adipose normal tissue in 3/8 patients. Concentration-time curves of unbound platinum in both the tissues followed the pattern of the curves in plasma, with exposure ratios of tissue versus plasma ranging from 0.64 to 1.46. Conclusions: Microdialysis can be successfully employed in ambulant patients for multiple days, which enables one to study tissue PK of anticancer drugs in normal and malignant tissues in more detail

Clinical efficiency research with expensive drugs:doing more with less investment

Novel innovative drugs have improved disease control, survival and quality of life for many patients. The costs of these drugs, however, are extremely high and threaten the long-term affordability of our health care system. Efficient use of existing drugs can decrease drug expenditure whilst improving patients' quality of life at the same time. Efficiency adjustments should not compromise treatment efficacy and therefore, clinical research on the matter is crucial. In this article, we demonstrate that efficiency research is feasible, as exemplified by the SONIA study. We make the case for a 'revolving fund' in which savings from one study are used to fund a next one. A revolving fund thus stimulates efficiency research and capitalizes research investments in the interest of both patients and society.</p

Doelmatigheidsonderzoek naar dure geneesmiddelen: Meer bereiken met lagere kosten

Novel innovative drugs have improved disease control, survival and quality of life for many patients. The costs of these drugs, however, are extremely high and threaten the long-term affordability of our health care system. Efficient use of existing drugs can decrease drug expenditure whilst improving patients' quality of life at the same time. Efficiency adjustments should not compromise treatment efficacy and therefore, clinical research on the matter is crucial. In this article, we demonstrate that efficiency research is feasible, as exemplified by the SONIA study. We make the case for a 'revolving fund' in which savings from one study are used to fund a next one. A revolving fund thus stimulates efficiency research and capitalizes research investments in the interest of both patients and society

Predictors for use of psychosocial services in patients with metastatic colorectal cancer receiving first line systemic treatment

Background: Patients with advanced disease experience high levels of psychological distress, yet there is low uptake of psychosocial services offered to patients who screened positive for distress. In this study we aimed to identify predictors for use of psychosocial services in patients with metastatic colorectal cancer (mCRC) receiving first line chemotherapy enrolled in a prospective cluster randomized trial (CRT). Methods: Patients completed measures on psychological distress, physical distress, and quality of life at baseline. Demographics, clinical characteristics at baseline and clinical events during treatment (e.g. severe adverse events, clinical benefit) were extracted from patient records. Patients reported psychosocial service utilization in- and outside the hospital after 10, 24 and 48 weeks of treatment. Multivariable logistic regression models were used to identify predictors for the use of psychosocial services. Results: Out of 349 patients, seventy patients (20.0%) used psychosocial support services during the follow-up period. Use of psychosocial services was associated with younger age, a higher educational level, presence of more pain (at baseline), and the expressed need to talk to a professional (at baseline). In addition, patients without progressive disease within the first ten weeks of treatment were more likely to use psychosocial services. Conclusions: One in five patients with mCRC receiving first line palliative treatment used psychosocial services during this prospective longitudinal CRT. Sociodemographic factors (age, education), clinical factors (pain and no progressive disease) and the expressed need to talk to a professional predicted use of psychosocial services. Identification of these predictors may contribute to the understanding of factors that determine the need for psychosocial services. Trial registration: Netherlands Trial Register NTR4034

Predicting outcome in older patients with cancer: Comprehensive geriatric assessment and clinical judgment

Objectives: Comprehensive Geriatric Assessment (CGA) has been incorporated into geriatric oncology to prevent unfavorable outcome from anticancer treatment. This study determined the value of CGA and medical oncologist's clinical judgment in predicting unfavorable outcome and explored whether treatment decisions can be based on CGA. Patients and Methods: In this prospective cohort study, a multidomain CGA was performed by a geriatric nurse and geriatrician in 110 consecutive patients aged ≥70 years, newly referred to a multidisciplinary oncology clinic. CGA domains included comorbidity, polypharmacy, mood, cognition, nutrition, functionality and physical performance. Medical oncologist's clinical judgment on expected tolerance of standard treatment was noted (N = 62). Unfavorable outcome was defined as any ≥grade three chemotherapy toxicity, dose reduction, postponement of treatment, death before start of treatment and early progression before first evaluation of treatment (N = 80). Results: CGA identified multidomain problems in 77 out of 110 patients (70.0%) and the medical oncologist had doubts about standard treatment tolerance in 30 out of 62 patients (48.4%). Unfavorable outcome occurred in 48 out of 80 patients (60%) who received anticancer treatment but could not be predicted by CGA, medical oncologists' clinical judgment or their combination. There was discrepancy between CGA and clinical judgment in 24 out of 62 patients (38.7%). Conclusion: Neither CGA, medical oncologist's clinical judgment or a combination could predict unfavorable outcome in our heterogeneous sample. CGA and clinical judgment did not align in more than one-third of patients